U.S. patent application number 14/117569 was filed with the patent office on 2014-07-24 for amorphous mirabegron and processes for crystal forms of mirabegron.
This patent application is currently assigned to DR. REDDY'S LABORATORIES LIMITED. The applicant listed for this patent is Rajesham Boge, Vishweshwar Peddy. Invention is credited to Rajesham Boge, Vishweshwar Peddy.
Application Number | 20140206729 14/117569 |
Document ID | / |
Family ID | 47177412 |
Filed Date | 2014-07-24 |
United States Patent
Application |
20140206729 |
Kind Code |
A1 |
Peddy; Vishweshwar ; et
al. |
July 24, 2014 |
AMORPHOUS MIRABEGRON AND PROCESSES FOR CRYSTAL FORMS OF
MIRABEGRON
Abstract
Aspects of the present invention relate to amorphous form of
mirabegron, amorphous solid dispersion of mirabegron, process for
its preparation, processes for preparation of a form crystal and
.beta. form crystal of mirabegron and pharmaceutical composition
thereof.
Inventors: |
Peddy; Vishweshwar;
(Hyderabad, IN) ; Boge; Rajesham; (Hyderabad,
IN) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Peddy; Vishweshwar
Boge; Rajesham |
Hyderabad
Hyderabad |
|
IN
IN |
|
|
Assignee: |
DR. REDDY'S LABORATORIES
LIMITED
Hyderabad
IN
|
Family ID: |
47177412 |
Appl. No.: |
14/117569 |
Filed: |
May 17, 2012 |
PCT Filed: |
May 17, 2012 |
PCT NO: |
PCT/IN12/00356 |
371 Date: |
November 13, 2013 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
61502911 |
Jun 30, 2011 |
|
|
|
Current U.S.
Class: |
514/370 ;
548/198 |
Current CPC
Class: |
A61P 13/00 20180101;
A61P 13/10 20180101; C07D 277/40 20130101; A61P 3/10 20180101; A61K
31/426 20130101 |
Class at
Publication: |
514/370 ;
548/198 |
International
Class: |
A61K 31/426 20060101
A61K031/426 |
Foreign Application Data
Date |
Code |
Application Number |
May 18, 2011 |
IN |
1678/CHE/2011 |
Claims
1-15. (canceled)
16. An amorphous mirabegron.
17. A process for preparing amorphous mirabegron of claim 16,
comprising: a) providing a solution of mirabegron in a solvent or
mixture of solvents; b) removing solvent from the solution obtained
in step a), and c) isolating an amorphous form of mirabegron.
18. An amorphous solid dispersion of mirabegron together with one
or more pharmaceutically acceptable carriers.
19. The amorphous solid dispersion of mirabegron of claim 18,
wherein the pharmaceutically acceptable carrier is at least one
selected from gelatines, ovalbumin, soybean proteins, gum arabic,
non-sucrose fatty acid esters, starches, modified starches,
cellulose, methylcellulose (MC), ethylcellulose (EC), hydroxy
ethylcellulose (HEC), hydroxypropylcellulose (HPC),
hydroxypropylmethylcellulose (HPMC), polycarbophil, polyethylene
glycol (PEG), polyethylene oxides, polyoxyalkylene derivatives,
polymethacrylates, polyvinyl pyrrolidone (PVP, povidone), polyvinyl
acetate (PVAc), PVP-vinylacetate-copolymer (PVP-VA), Kollidon VA 64
(a vinylpyrrolidone-vinyl acetate copolymer), lactose, sorbitol,
mannitol, maltitol, saccharose, Isomalt, cyclodextrins such as
.alpha.-cyclodextrins, .beta.-cyclodextrins, .gamma.-cyclodextrins
and hydroxyl-propyl-.beta.-cyclodextrins,
sodiumcarboxymethylcellulose, sodium alginate, xantham gum,
caavageenan, locust bean gum (ceratonia), chitosan, guar gum,
cross-linkedhighamylase starch, and cross-linked polyacrylic acid
(carbopol).
20. An amorphous solid dispersion of mirabegron of claim 18,
wherein the pharmaceutically acceptable carrier is povidone.
21. The amorphous solid dispersion of mirabegron of claim 18
wherein the ratio of at least one pharmaceutically carrier to the
mirabegron is at least about 1:2 (w/w) to about (2:1) (w/w).
22. A process for preparing the amorphous solid dispersion of
mirabegron of claim 18, comprising: a) providing a solution of
mirabegron in combination with one or more pharmaceutically
acceptable carriers in a solvent or mixture of solvents; b)
removing the solvent from the solution or suspension obtained in
step a) or combining the solution obtained in step a) with an
anti-solvent, and c) isolating solid dispersion of amorphous
mirabegron together with one or more pharmaceutically acceptable
carrier.
23. A solid pharmaceutical formulation comprising the amorphous
mirabegron of claim 16 and one or more pharmaceutically acceptable
carrier.
24. A solid pharmaceutical formulation comprising the solid
dispersion of amorphous mirabegron of claim 18 and one or more
pharmaceutically acceptable carrier.
25. A method of treating a disease associated with overactive
bladder, said method comprising administering to a subject in need
thereof amorphous mirabegron of claim 16 together with at least one
pharmaceutically acceptable carrier.
26. A method of treating a disease associated with overactive
bladder, said method comprising administering to a subject in need
thereof amorphous solid dispersion of mirabegron of claim 18
together with at least one pharmaceutically acceptable carrier.
27. A process for the preparation of .alpha.-form crystal of
mirabegron comprising: (A) i) dissolving mirabegron in a solvent
selected from methanol, ethanol, tetrahydrofuran, ethyl acetate,
toluene or mixtures thereof to provide a solution; ii) cooling the
solution obtained in step a), and iii) isolating .alpha.-form
crystal of mirabegron; or (B) i) dissolving mirabegron in a mixture
of methanol and water to provide a solution; ii) cooling the
solution obtained in step a), and iii) isolating .alpha.-form
crystal of mirabegron; or (C) i) providing a solution of mirabegron
in a solvent selected from tetrahydrofuran, methanol, ethanol,
acetone, acetonitrile, 1,4-dioxane, methyl isobutyl ketone,
chlorobenzene or mixtures thereof; ii) combining the solution
obtained in step a) with an anti-solvent selected from cyclohexane,
methylcyclohexane, n-heptane, diisopropyl ether, methyl tertiary
butyl ether, toluene, water, provided that when methanol is used as
a solvent then anti-solvent is other than water; and iii) isolating
.alpha.-form crystal of mirabegron.
28. A solid pharmaceutical formulation comprising .alpha.-form
crystal of mirabegron obtained according to claim 27 and one or
more pharmaceutically acceptable carrier.
29. A method of treating a disease associated with overactive
bladder, which method comprises administering to a subject in need
thereof .alpha.-form crystal of mirabegron obtained according to
claim 27.
Description
[0001] Aspects of the present invention relate to amorphous form of
mirabegron, amorphous solid dispersion of mirabegron, process for
its preparation, processes for the preparation of .alpha.-form
crystal and .beta.-form crystal of mirabegron and pharmaceutical
composition comprising thereof.
BACKGROUND
[0002] Mirabegron is chemically described as
(R)-2-(2-aminothiazol-4-yl)-4'-[2-[(2-hydroxy-2-phenylethyl)amino]ethyl]--
acetanilide or
2-amino-N-[4-[2-[[(2R)-2-hydroxy-2-phenylethyl]amino]ethyl]phenyl]-4-thia-
zoleacetamide. It has the structure of formula (I).
##STR00001##
[0003] Mirabegron is an orally active beta-3 adrenoceptor agonist
and is under pre-registration in USA and Europe for the potential
treatment of urinary frequency, urinary incontinence, or urgency
associated with overactive bladder by Astellas Pharma. Mirabegron
is approved in Japan. U.S. Pat. No. 6,346,532 B1 discloses
mirabegron or a salt thereof and process for its preparation. U.S.
Pat. No. 7,342,117 B2 discloses .alpha.-form crystal and
.beta.-form crystal of mirabegron.
[0004] Amorphous forms can be thought of as liquids that have been
solidified by the removal of thermal energy or a solvent, in a
manner that circumvents crystallization. The amorphous form can
have different solubility, stability, and mechanical behavior that
can be exploited by pharmaceutical scientists. The solubility of a
given solid is a sum of crystal packing energy, cavitation, and
solvation energy. Different crystalline forms of a given drug will
have different crystal packing energies. The amorphous forms of the
same drug require minimal packing energy disruption when dissolving
due to absence of an ordered crystal lattice. Thus, the amorphous
forms provide the maximal solubility advantage as compared to the
crystalline forms of a drug. The `apparent solubility` and
dissolution advantage offered by these systems is a vital approach
to enhance bioavailability of poorly water soluble drugs.
[0005] There always remains a need to provide the new polymorphic
forms of mirabegron and processes for making the new polymorphic
forms.
[0006] The present invention provides amorphous mirabegron and
amorphous solid dispersion of mirabegron which can be used in the
pharmaceutical composition.
[0007] U.S. Pat. No. 7,342,117 B2 discloses the preparation of
.alpha.-form crystal and .beta.-form crystal of mirabegron.
[0008] The methods for the preparation of .alpha.-form crystal and
.beta.-form crystal of mirabegron as per the literature involves
the use of rapid cooling, use of seed material and use of solvents
water and ethanol only.
[0009] The methods for the preparation of .alpha.-form crystal and
.beta.-form crystal of mirabegron described in the literature
suffer from one or more drawbacks such as reproducibility, use of
seed material, less yield, limited solvents, which does not result
an industrially feasible process.
[0010] Therefore, there is a need to provide simple, reproducible,
environment friendly, cost effective, industrially feasible
processes for the preparation of .alpha.-form crystal and
.beta.-form crystal of mirabegron.
SUMMARY
[0011] In an aspect, the present invention provides an amorphous
form of mirabegron.
[0012] In an aspect, the present invention provides an amorphous
form of mirabegron characterized by a powder X-ray diffraction
(PXRD) pattern, substantially as illustrated by FIG. 1.
[0013] In an aspect, the present invention provides a process for
the preparation of an amorphous form of mirabegron, comprising:
[0014] a) providing a solution of mirabegron in a solvent or
mixture of solvents;
[0015] b) removing the solvent from the solution obtained in step
a), and
[0016] c) isolating an amorphous form of mirabegron.
[0017] In an aspect, the present invention provides a
pharmaceutical composition comprising amorphous form of mirabegron
along with one or more pharmaceutically acceptable carriers,
excipients, or diluents.
[0018] In an aspect, the present invention provides solid
dispersion of amorphous mirabegron together with one or more
pharmaceutically acceptable carriers.
[0019] In an aspect, the present invention provides solid
dispersion of amorphous mirabegron together with povidone.
[0020] In an aspect, the present invention provides solid
dispersion of amorphous mirabegron together with povidone
characterized by a powder X-ray diffraction (PXRD) pattern,
substantially as illustrated by FIG. 2. or FIG. 3.
[0021] In an aspect, the present invention provides a process for
preparing a solid dispersion of amorphous mirabegron together with
one or more pharmaceutically acceptable carriers, comprising:
[0022] a) providing a solution or suspension of mirabegron in
combination with one or more pharmaceutically acceptable carriers
in a solvent or mixture of solvents;
[0023] b) removing the solvent from the solution or suspension
obtained in step a) or combining the solution obtained in step a),
with an anti-solvent, and
[0024] c) isolating solid dispersion of amorphous mirabegron
together with one or more pharmaceutically acceptable carrier.
[0025] In an aspect, the present invention provides a process for
the preparation of .alpha.-form crystal of mirabegron
comprising:
[0026] a) providing a solution of mirabegron in a solvent selected
from methanol, ethanol, tetrahydrofuran, ethyl acetate, toluene or
mixtures thereof;
[0027] b) cooling the solution obtained in step a), and
[0028] c) isolating .alpha.-form crystal of mirabegron.
[0029] In an aspect, the present invention provides a process for
the preparation of .alpha.-form crystal of mirabegron,
comprising:
[0030] a) dissolving mirabegron in a mixture of methanol and water
to provide a solution;
[0031] b) cooling the solution obtained in step a), and
[0032] c) isolating .alpha.-form crystal of mirabegron.
[0033] In an aspect, the present invention provides a process for
the preparation of .alpha.-form crystal of mirabegron,
comprising:
[0034] a) providing a solution of mirabegron in a solvent selected
from tetrahydrofuran, methanol, ethanol, acetone, acetonitrile,
1,4-dioxane, methyl isobutyl ketone, chlorobenzene or mixtures
thereof;
[0035] b) adding an anti-solvent to the solution of step a),
selected from cyclohexane, methylcyclohexane, n-heptane,
diisopropyl ether, methyl tertiary butyl ether, toluene, water,
provided that when methanol is used as a solvent then anti-solvent
is other than water; and
[0036] c) isolating .alpha.-form crystal of mirabegron.
[0037] In an aspect, the present invention provides a process for
the preparation of .alpha.-form crystal of mirabegron
comprising:
[0038] a) dissolving mirabegron in acetone to provide a
solution;
[0039] b) adding the solution obtained from step a) to
methylcyclohexane, and
[0040] c) isolating .alpha.-form crystal of mirabegron.
[0041] In an aspect, the present invention provides a process for
the preparation of .alpha.-form crystal of mirabegron
comprising:
[0042] a) providing a solution of mirabegron in a solvent or
mixture of solvents, and
[0043] b) isolating .alpha.-form crystal of mirabegron by the slow
solvent evaporation.
[0044] In an aspect, the present invention provides a process for
the preparation of .beta.-form crystal of mirabegron
comprising:
[0045] a) dissolving mirabegron in methyl isobutyl ketone to
provide a solution;
[0046] b) cooling the solution obtained in step a), and
[0047] c) isolating .beta.-form crystal of mirabegron.
[0048] In an aspect, the present invention provides a process for
the preparation of .beta.-form crystal of mirabegron
comprising:
[0049] a) providing a solution of mirabegron in a solvent selected
from tetrahydrofuran, formamide, N,N-dimethylformamide,
N,N-dimethylacetamide, 2-methoxyethanol, morpholine or mixtures
thereof;
[0050] b) adding the solution obtained from step a) to an
anti-solvent selected from methylcyclohexane, n-heptane, toluene,
water, and
[0051] c) isolating .beta.-form crystal of mirabegron.
[0052] In an aspect, the present invention provides a process for
the preparation of .beta.-form crystal of mirabegron
comprising:
[0053] a) providing a solution of mirabegron in a solvent selected
from dimethylsulfoxide, morpholine, N-methylpyrolidone, ethyl
acetate, or mixtures thereof;
[0054] b) adding an anti-solvent to the solution obtained from step
a) selected from the group of n-heptane and water, and
[0055] c) isolating .beta.-form crystal of mirabegron.
[0056] In an aspect, the present invention provides a process for
the preparation of .beta.-form crystal of mirabegron
comprising:
[0057] a) dissolving mirabegron in methanol to provide a
solution;
[0058] b) adding water to the solution obtained in step a)
[0059] c) isolating .beta.-form crystal of mirabegron.
[0060] In an aspect, the present invention provides pharmaceutical
formulations comprising solid dispersions of amorphous mirabegron
together with one or more pharmaceutically acceptable
excipients.
BRIEF DESCRIPTION OF THE DRAWINGS
[0061] FIG. 1 is an illustration of a powder X-ray diffraction
(PXRD) pattern of an amorphous form of mirabegron prepared
according to Example 1.
[0062] FIG. 2 is an illustration of a powder X-ray diffraction
(PXRD) pattern of solid dispersion of amorphous mirabegron prepared
according to Example 2.
[0063] FIG. 3 is an illustration of a powder X-ray diffraction
(PXRD) pattern of solid dispersion of amorphous mirabegron prepared
according to Example 3.
DETAILED DESCRIPTION
[0064] In an aspect, the present invention provides an amorphous
form of mirabegron.
[0065] In an aspect, the present invention provides an amorphous
form of mirabegron characterized by a powder X-ray diffraction
(PXRD) pattern, substantially as illustrated by FIG. 1.
[0066] In an aspect, the present invention provides a process for
the preparation of an amorphous form of mirabegron, comprising:
[0067] a) providing a solution of mirabegron in a solvent or
mixture of solvents;
[0068] b) removing the solvent from the solution obtained in step
a), and
[0069] b) isolating an amorphous form of mirabegron.
[0070] Step a) involves providing a solution of mirabegron in a
solvent or mixture of solvents. Providing a solution in step a)
includes:
[0071] i) solutions obtained from reaction mixtures in the final
stage of processes for preparing the mirabegron or
[0072] ii) dissolving mirabegron in a suitable solvent or mixture
of solvents.
[0073] Suitable solvents that may be used in step a) include, but
are not limited to, alcohol solvents; ketone solvents; halogenated
hydrocarbon solvents; ester solvents; nitrile solvents; polar
aprotic solvents; water; or mixtures thereof.
[0074] The dissolution temperatures may range from about 0.degree.
C. to about the reflux temperature of the solvent, depending on the
solvent used for dissolution, as long as a clear solution of
mirabegron is obtained without affecting its quality. The solution
may optionally be treated with carbon, flux-calcined diatomaceous
earth (Hyflow), or any other suitable material to remove color
and/or to clarify the solution.
[0075] Optionally, the solution obtained above may be filtered to
remove any insoluble-particles. The solution may be filtered by
passing through paper, glass fiber, or other membrane material, or
a bed of a clarifying agent such as Celite.RTM. or Hyflow.
Depending upon the equipment used and the concentration and
temperature of the solution, the filtration apparatus may need to
be preheated to avoid premature crystallization.
[0076] Step b) involves the removal of solvents from the solution
obtained from step a). Suitable techniques which may be used for
the removal of the solvent include using a rotational distillation
device such as a Buchi.RTM. Rotavapor.RTM., spray drying, agitated
thin film drying, freeze drying (lyophilization), and the like, or
any other suitable technique.
[0077] The solvent may be removed, optionally under reduced
pressures, at temperatures less than about 100.degree. C., less
than about 60.degree. C., less than about 40.degree. C., less than
about 20.degree. C., less than about 0.degree. C., less than about
-20.degree. C., less than about -40.degree. C., less than about
-60.degree. C., less than about -80.degree. C., or any other
suitable temperatures.
[0078] Freeze drying (lyophilization) may be carried out by
freezing a solution of mirabegron at low temperatures and reducing
the pressure as required for removing the solvent from the frozen
solution of mirabegron. Temperatures that may be required to freeze
the solution, depending on the solvent chosen to make the solution
of mirabegron, may range from about -80.degree. C. to about
0.degree. C., or up to about 20.degree. C. Temperatures that may be
required to remove the solvent from the frozen solution may be less
than about 20.degree. C., less than about 0.degree. C., less than
about -20.degree. C., less than about -40.degree. C., less than
about -60.degree. C., less than about -80.degree. C., or any other
suitable temperatures.
[0079] Step c) involves the isolation of an amorphous form of
mirabegron from the solution of step b). The compound obtained from
step b) may be collected using techniques such as by scraping, or
by shaking the container, or adding solvent to make slurry followed
by filtration, or other techniques specific to the equipment
used.
[0080] In embodiments of step c) the amorphous obtained from step
b) may be optionally dried. Drying may be suitably carried out in a
tray dryer, vacuum oven, Buchi.RTM. Rotavapor.RTM., air oven,
fluidized bed dryer, spin flash dryer, flash dryer, or the like.
The drying may be carried out at atmospheric pressure or under
reduced pressures at temperatures of less than about 100.degree.
C., less than about 60.degree. C., less than about 40.degree. C.,
or any other suitable temperatures. The drying may be carried out
for any time period required for obtaining a desired quality, such
as from about 15 minutes to 10 hours or longer.
[0081] In an aspect, the present invention provides solid
dispersion of amorphous mirabegron together with one or more
pharmaceutically acceptable carriers.
[0082] In an aspect, the amorphous solid dispersion of mirabegron
and at least one pharmaceutically acceptable carrier according to
the present invention has a ratio of at least one pharmaceutically
acceptable carrier to the mirabegron at least about 1:2 to about
2:1 (w/w).
[0083] In an aspect, the present invention provides solid
dispersion of amorphous mirabegron together with one or more
pharmaceutically acceptable carrier characterized by a powder X-ray
diffraction (PXRD) pattern, substantially as illustrated by FIG. 2
or substantially as illustrated by FIG. 3.
[0084] In an aspect, the present invention provides a process for
preparing a solid dispersion of amorphous mirabegron together with
one or more pharmaceutically acceptable carriers, comprising:
[0085] a) providing a solution or suspension of mirabegron in
combination with one or more pharmaceutically acceptable carriers
in a solvent or mixture of solvents;
[0086] b) removing the solvent from the solution or suspension
obtained in step a) or combining the solution obtained in step a),
with an anti-solvent, and
[0087] c) isolating solid dispersion of amorphous mirabegron
together with one or more pharmaceutically acceptable carrier.
[0088] Step a) involves providing a solution or suspension of
mirabegron in combination with one or more pharmaceutically
acceptable carriers in a solvent or mixture of solvents.
[0089] In aspects, step a) may involve forming a solution of
mirabegron together with one or more pharmaceutically acceptable
carriers. In aspects, a carrier is one which enhances stability of
the amorphous solid upon removal of the solvent.
[0090] Providing the solution in step a) includes:
[0091] i) solutions obtained from reaction mixtures in the final
stage of processes for preparing the mirabegron, if desired, after
addition of one or more pharmaceutically acceptable carriers;
or
[0092] ii) dissolution of mirabegron in a suitable solvent, either
alone or in combination with one or more pharmaceutically
acceptable carriers.
[0093] Pharmaceutically acceptable carriers that may be used for
the preparation of solid dispersions of mirabegron of the present
invention include, but are not limited to: water soluble sugar
derivatives including any pharmaceutically acceptable water soluble
sugar excipients, preferably having low hygroscopicity, which
include, but are not limited to, mannitol, lactose, fructose,
sorbitol, xylitol, maltodextrin, dextrates, dextrins, lactitol, or
the like; pharmaceutical hydrophilic carriers such as
polyvinylpyrrolidones (homopolymers or copolymers of N-vinyl
pyrrolidone), gums, cellulose derivatives (including hydroxypropyl
methylcelluloses, hydroxypropyl celluloses, microcrystalline
celluloses and others), polymers of carboxymethyl celluloses,
cyclodextrins, gelatins, hypromellose phthalates, sugars,
polyhydric alcohols, polyethylene glycols, polyethylene oxides,
polyoxyethylene derivatives, polyvinyl alcohols, propylene glycol
derivatives, or the like; or organic amines such as alkyl amines
(primary, secondary, and tertiary), aromatic amines, alicyclic
amines, cyclic amines, aralkyl amines, hydroxylamine or its
derivatives, hydrazine or its derivatives, and guanidine or, its
derivatives. The use of mixtures of more than one of the
pharmaceutical excipients to provide desired release profiles or
for the enhancement of stability is within the scope of this
invention. Also, all viscosity grades, molecular weights,
commercially available products, their copolymers, and mixtures are
all within the scope of this invention without limitation.
[0094] When the solution or suspension of mirabegron is prepared
together with a pharmaceutically acceptable carrier, the order of
charging different materials to the solution is not critical for
obtaining the desired solid dispersion. A specific order may be
preferred with respect to the equipment being used and will be
easily determined by a person skilled in the art. Mirabegron or
pharmaceutically acceptable carrier may be completely soluble in
the solvent or they may form a suspension. In embodiments,
mirabegron and the pharmaceutically acceptable carrier may be
separately dissolved either in the same solvent or in different
solvents, and then combined to form a mixture.
[0095] Suitable solvents that may be used in step a) include, but
are not limited to, alcohol solvents; ketone solvents; halogenated
hydrocarbon solvents; ester solvents; nitrile solvents; polar
aprotic solvents; water; or mixtures thereof.
[0096] The dissolution temperatures may range from 0.degree. C. to
about the reflux temperature of the solvent, depending on the
solvent used for dissolution, as long as a clear solution of
mirabegron is obtained without affecting its quality. The solution
may optionally be treated with carbon, flux-calcined diatomaceous
earth (Hyflow), or any other suitable material to remove color
and/or to clarify the solution.
[0097] Optionally, the solution obtained above may be filtered to
remove any insoluble particles. The solution may be filtered by
passing through paper, glass fiber, or other membrane material, or
a bed of a clarifying agent such as Celite.RTM. or Hyflow.
Depending upon the equipment used and the concentration and
temperature of the solution, the filtration apparatus may need to
be preheated to avoid premature crystallization.
[0098] Step b) involves the removal of solvents from the solution
obtained from step a). In an aspect, suitable techniques which may
be used for the removal of the solvent include using a rotational
distillation device such as a Buchi.RTM. Rotavapor.RTM., spray
drying, agitated thin film drying, freeze drying (lyophilization),
atmospheric distillation, vacuum distillation, and the like, or any
other suitable technique.
[0099] The solvent may be removed, optionally under reduced
pressures, at temperatures less than about 100.degree. C., less
than about 60.degree. C., less than about 40.degree. C., less than
about 20.degree. C., less than about 0.degree. C., less than about
-20.degree. C., less than about -40.degree. C., less than about
-60.degree. C., less than about -80.degree. C., or any other
suitable temperatures.
[0100] Freeze drying (lyophilization) may be carried out by
freezing a solution of mirabegron at low temperatures and reducing
the pressure as required for removing the solvent from the frozen
solution of mirabegron. Temperatures that may be required to freeze
the solution, depending on the solvent chosen to make the solution
of mirabegron, may range from about -80.degree. C. to about
0.degree. C., or up to about 20.degree. C. Temperatures that may be
required to remove the solvent from the frozen solution may be less
than about 20.degree. C., less than about 0.degree. C., less than
about -20.degree. C., less than about -40.degree. C., less than
about -60.degree. C., less than about -80.degree. C., or any other
suitable temperatures.
[0101] In another aspect, isolation may also be effected by
combining the solution of step a) with a suitable anti-solvent
optionally comprising one or more pharmaceutically acceptable
carriers. Adding the solution obtained in step a) to the
anti-solvent, or adding an anti-solvent to the solution obtained in
step a), to effect the crystallization process are both within the
scope of the present invention. Optionally, the addition may be
carried out after concentrating the solution obtained in step a).
Suitable anti-solvents that may be used include, but are not
limited to: water; aliphatic or alicyclic hydrocarbon solvents;
aromatic hydrocarbon solvents; ether solvents; or mixtures
thereof.
[0102] In embodiments of step c) involves isolation of solid
dispersion of amorphous mirabegron together with one or more
pharmaceutically acceptable carriers from the solution of step
a).
[0103] The compound obtained from step c) may be collected using
techniques such as by scraping, or by shaking the container, or
filtration, or adding solvent for making slurry followed by
filtration, or other techniques specific to the equipment used. The
product thus isolated may be optionally further dried to afford an
amorphous form of mirabegron together with a pharmaceutically
acceptable excipients. Drying may be suitably carried out in a tray
dryer, vacuum oven, Buchi.RTM. Rotavapor.RTM., air oven, fluidized
bed dryer, spin flash dryer, flash dryer, or the like. The drying
may be carried out at atmospheric pressure or under reduced
pressures at temperatures of less than about 100.degree. C., less
than about 60.degree. C., less than about 40.degree. C., or any
other suitable temperatures. The drying may be carried out for any
time period required for obtaining a desired quality, such as from
about 15 minutes to 10 hours or longer.
[0104] Examples of amorphous solid, dispersions of mirabegron
together with a pharmaceutically acceptable carrier obtained using
the above process are characterized by their powder X-ray
diffraction ("PXRD") patterns substantially as illustrated by FIGS.
2 and 3, respectively.
[0105] The solid dispersions differ from physical mixtures of
amorphous mirabegron and one or more pharmaceutically acceptable
carriers, so that individual particles of the components cannot be
distinguished using techniques such as optical microscopy. In
instances, the solid dispersions contain the components on a
molecular level, such as in the nature of solid solutions.
[0106] In an aspect, the present invention provides a process for
the preparation of .alpha.-form crystal of mirabegron
comprising:
[0107] a) providing a solution of mirabegron in a solvent selected
from methanol, ethanol, tetrahydrofuran, ethyl acetate, toluene or
mixtures thereof;
[0108] b) cooling the solution obtained in step a), and
[0109] c) isolating .alpha.-form crystal of mirabegron.
[0110] In embodiments of step a) the solution of mirabegron can be
obtained by dissolving mirabegron in a solvent selected from
methanol, ethanol, tetrahydrofuran, ethyl acetate, toluene or
mixtures thereof. Stirring and heating may be used to reduce the
time required for the dissolution process.
[0111] In embodiments, a solution of mirabegron may be filtered to
make it clear, free of unwanted particles. In embodiments, the
obtained solution may be optionally treated with an adsorbent
material, such as carbon and/or hydrose; to remove colored
components, etc., before filtration.
[0112] In embodiments of step b) the solution obtained in step a)
may be cooled to room temperature to produce .alpha.-form crystal
of mirabegron. Preferably the solution may be cooled to 0-5.degree.
C. to produce .alpha.-form crystal of mirabegron. The cooling may
be done slowly or rapidly. Preferably the cooling can be done
slowly.
[0113] In embodiments of step c), .alpha.-form crystal of
mirabegron can be isolated by the techniques known in the art such
as filtration. In embodiments, .alpha.-form crystal of mirabegron
can be optionally dried at the suitable temperature and pressure
for a suitable time.
[0114] In an aspect, the present invention provides a process for
the preparation of .alpha.-form crystal of mirabegron,
comprising:
[0115] a) dissolving mirabegron in a mixture of methanol and water
to provide a solution;
[0116] b) cooling the solution obtained in step a), and
[0117] c) isolating .alpha.-form crystal of mirabegron.
[0118] In embodiments of step a) the solution of mirabegron can be
obtained by dissolving mirabegron in a mixture of methanol and
water. In embodiments of step a) the ratio of methanol and water
may be used in any suitable ratio. Stirring and heating may be used
to reduce the time required for the dissolution process.
[0119] In embodiments, a solution of mirabegron may be filtered to
make it clear, free of unwanted particles. In embodiments, the
obtained solution may be optionally treated with an adsorbent
material, such as carbon and/or hydrose, to remove colored
components, etc., before filtration.
[0120] In embodiments of step b) the solution obtained in step a)
may be cooled to about 0.degree. C. to about 40.degree. C. to
produce .alpha.-form crystal of mirabegron. In embodiments, the
solution may be cooled to about 10.degree. C. to 30.degree. C. The
cooling may be done slowly or rapidly. Preferably the cooling can
be done slowly.
[0121] In embodiments of step c), .alpha.-form crystal of
mirabegron can be isolated by the techniques known in the art such
as filtration. In embodiments, .alpha.-form crystal of mirabegron
can be optionally dried at the suitable temperature and pressure
for a suitable time.
[0122] In an aspect, the present invention provides a process for
the preparation of .alpha.-form crystal of mirabegron,
comprising:
[0123] a) providing a solution of mirabegron in a solvent selected
from tetrahydrofuran, methanol, ethanol, acetone, acetonitrile,
1,4-dioxane, methyl isobutyl ketone, chlorobenzene or mixtures
thereof;
[0124] b) adding an anti-solvent to the solution obtained from step
a) selected from cyclohexane, methylcyclohexane, n-heptane,
diisopropyl ether, methyl tertiary butyl ether, toluene, water,
provided that when methanol is used as a solvent then anti-solvent
is other than water; and
[0125] c) isolating .alpha.-form crystal of mirabegron.
[0126] Step a) involves the preparation of a solution of mirabegron
by dissolving the mirabegron in a suitable inert solvent. The
suitable solvent for making a solution can be selected from
tetrahydrofuran, methanol, ethanol, acetone, acetonitrile,
1,4-dioxane, methyl isobutyl ketone, chlorobenzene or mixtures
thereof. In embodiments, a solution of mirabegron can be prepared
at any suitable temperatures, such as about 0.degree. C. to about
the reflux temperature of the solvent used. Stirring and heating
may be used to reduce the time required for the dissolution
process.
[0127] In embodiments, a solution of mirabegron may be filtered to
make it clear, free of unwanted particles. In embodiments, the
obtained solution may be optionally treated with an adsorbent
material, such as carbon and/or hydrose, to remove colored
components, etc., before filtration.
[0128] In embodiments of step b) the anti-solvent may be added to
the solution obtained in step a). The anti-solvent can be added to
the solution drop-wise, lot wise in one lot or more lots or
rapidly. The anti-solvents may be selected from cyclohexane,
methylcyclohexane, n-heptane, diisopropyl ether, methyl tertiary
butyl ether, toluene, water. In embodiments, when methanol is used
as a solvent in step a) then anti-solvent can be other than
water.
[0129] In embodiments, slurry obtained by the precipitation
comprising .alpha.-form crystal of mirabegron and inert solvent can
be maintained at any suitable temperatures, such as about
-10.degree. C. to about 40.degree. C., or about 0.degree. C. to
about 35.degree. C. In embodiments, slurry comprising mirabegron
can be maintained for about 30 minutes to about 10 hours, or
longer.
[0130] In embodiments, the .alpha.-form crystal of mirabegron can
be isolated using any techniques, such as decantation, filtration
by gravity or suction, centrifugation, or the solvent can be
evaporated from the mass to obtain the desired product, and
optionally the solid can be washed with a solvent, such as an
anti-solvent or the solvent, to reduce the amount of entrained
impurities.
[0131] In embodiments, the .alpha.-form crystal of mirabegron that
is isolated can be dried at suitable temperatures, and atmospheric
or reduced pressures, for about 1-50 hours, or longer, using any
types of drying equipment, such as a tray dryer, vacuum oven, air
oven, fluidized bed dryer, spin flash dryer, flash dryer, and the
like. Drying temperatures and times will be sufficient to achieve
desired product purity.
[0132] In an aspect, the present invention provides a process for
the preparation of .alpha.-form crystal of mirabegron
comprising:
[0133] a) dissolving mirabegron in acetone to provide a
solution;
[0134] b) adding the solution obtained from step a) to
methylcyclohexane, and
[0135] c) isolating .alpha.-form crystal of mirabegron.
[0136] Step a) involves the preparation of solution of mirabegron
by dissolving the mirabegron in acetone. In embodiments, a solution
of mirabegron can be prepared at any suitable temperatures, such as
about 0.degree. C. to about the reflux temperature of the solvent
used. Stirring and heating may be used to reduce the time required
for the dissolution process.
[0137] In embodiments, a solution of mirabegron may be filtered to
make it clear, free of unwanted particles. In embodiments, the
obtained solution may be optionally treated with an adsorbent
material, such as carbon and/or hydrose, to remove colored
components, etc., before filtration.
[0138] In embodiments of step b) the solution obtained in step a)
may be added to methylcyclohexane. The solution can be added to the
methylcyclohexane drop-wise, lot wise in one or more lots or
rapidly.
[0139] In embodiments, slurry obtained by the precipitation
comprising .alpha.-form crystal of mirabegron and inert solvent can
be maintained at any suitable temperatures, such as about
-10.degree. C. to about 40.degree. C., or about 0.degree. C. to
about 35.degree. C. In embodiments, slurry comprising mirabegron
can be maintained for about 30 minutes to about 10 hours, or
longer.
[0140] In embodiments, the .alpha.-form crystal of mirabegron can
be isolated using any techniques, such as decantation, filtration
by gravity or suction, centrifugation, or the solvent can be
evaporated from the mass to obtain the desired product, and
optionally the solid can be washed with a solvent, such as an
anti-solvent or the solvent, to reduce the amount of entrained
impurities.
[0141] In embodiments, the .alpha.-form crystal of mirabegron that
is isolated can be dried at suitable temperatures, and atmospheric
or reduced pressures, for about 1-50 hours, or longer, using any
types of drying equipment, such as a tray dryer, vacuum oven, air
oven, fluidized bed dryer, spin flash dryer, flash dryer, and the
like. Drying temperatures and times will be sufficient to achieve
desired product purity.
[0142] In an aspect, the present invention provides a process for
the preparation of .alpha.-form crystal of mirabegron
comprising:
[0143] a) providing a solution of mirabegron in a solvent or
mixture of solvents, and
[0144] b) isolating the .alpha.-form crystal of mirabegron by the
slow solvent evaporation.
[0145] In embodiments of step a), mirabegron can be dissolved in
any suitable inert solvent. The suitable solvent for making a
solution can be selected from the group of 2-butanol, ethanol,
isopropyl alcohol, ethyl acetate, tetrahydrouran, chlorobenzene or
any mixtures of two or more thereof. In embodiments, a solution of
mirabegron can be prepared at any suitable temperatures, such as
about 0.degree. C. to about the reflux temperature of the solvent
used. Stirring and heating may be used to reduce the time required
for the dissolution process.
[0146] In embodiments, a solution of mirabegron may be filtered to
make it clear, free of unwanted particles. In embodiments, the
obtained solution may be optionally treated with an adsorbent
material, such as carbon and/or hydrose, to remove colored
components, etc., before filtration.
[0147] In embodiments, the solution obtained from step a) may be
kept for the evaporation of the solvent. In embodiment the solvent
may be evaporated at the temperature about 10.degree. C. to about
50.degree. C. In embodiments, the solvent may be evaporated by
keeping the solution in open at the room temperature till the
evaporation of the solvent.
[0148] In embodiments, .alpha.-form crystal of mirabegron that is
isolated can be dried at suitable temperatures, and atmospheric or
reduced pressures, for about 1-50 hours, or longer, using any types
of drying equipment, such as a tray dryer, vacuum oven, air oven,
fluidized bed dryer, spin flash dryer, flash dryer, and the like.
Drying temperatures and times will be sufficient to achieve desired
product purity.
[0149] In a further aspect .alpha.-form crystal of mirabegron can
be prepared by slurring the crude mirabegron in a suitable solvent.
The crude mirabegron can be crystalline, mixture of crystalline and
amorphous, solvate or hydrate.
[0150] In an aspect, the present invention provides a process for
the preparation of .beta.-form crystal of mirabegron
comprising:
[0151] a) dissolving mirabegron in methyl, isobutyl ketone to
provide a solution;
[0152] b) cooling the solution obtained in step a), and
[0153] c)isolating .beta.-form crystal of mirabegron.
[0154] In embodiments of step a) the solution of mirabegron can be
obtained by dissolving the mirabegron in methyl isobutyl ketone.
Stirring and heating may be used to reduce the time required for
the dissolution process.
[0155] In embodiments, a solution of mirabegron may be filtered to
make it clear, free of unwanted particles. In embodiments, the
obtained solution may be optionally treated with an adsorbent
material, such as carbon and/or hydrose, to remove colored
components, etc., before filtration.
[0156] In embodiments of step b) the solution obtained in step a)
may be cooled to 0 to 5.degree. C. to produce the .beta.-form
crystal of mirabegron. The cooling may be done slowly or rapidly.
Preferably the cooling can be slowly.
[0157] In embodiments of step c), the .beta.-form crystal of
mirabegron can be isolated by the techniques known in the art such
as filtration. In embodiments, the .beta.-form crystal of
mirabegron can be optionally dried at the suitable temperature and
pressure for a suitable time.
[0158] In an aspect, the present invention provides a process for
the preparation of .beta.-form crystal of mirabegron
comprising:
[0159] a) providing a solution of mirabegron in a solvent selected
from tetrahydrofuran, formamide, N,N-dimethylformamide,
N,N-dimethylacetamide, 2-methoxyethanol, morpholine or mixtures
thereof
[0160] b) adding the solution obtained from step a) to an
anti-solvent selected from methylcyclohexane, n-heptane, toluene
and water, and
[0161] c) isolating .beta.-form crystal of mirabegron.
[0162] Step a) involves the preparation of solution of mirabegron
by dissolving the mirabegron in a suitable inert solvent. The
suitable solvent for making a solution can be selected from
tetrahydrofuran, formamide, N,N-dimethylformamide,
N,N-dimethylacetamide, 2-methoxyethanol, morpholine or mixtures
thereof. In embodiments, a solution of mirabegron can be prepared
at any suitable temperatures, such as about 0.degree. C. to about
the reflux temperature of the solvent used. Stirring and heating
may be used to reduce the time required for the dissolution
process.
[0163] In embodiments, a solution of mirabegron may be filtered to
make it clear, free of unwanted particles. In embodiments, the
obtained solution may be optionally treated with an adsorbent
material, such as carbon and/or hydrose, to remove colored
components, etc., before filtration.
[0164] In embodiments of step b) the solution obtained in step a)
may be added to a suitable anti-solvent. The solution can be added
to the anti-solvent drop-wise, lot wise in one or more lots or
rapidly. The anti-solvents may be selected from the group of
methylcyclohexane, n-heptane, toluene and water.
[0165] In embodiments, slurry obtained by the precipitation
comprising .beta.-form crystal of mirabegron and inert solvent can
be maintained at any suitable temperatures, such as about
-10.degree. C. to about 40.degree. C., or about 0.degree. C. to
about 35.degree. C. In embodiments, slurry comprising mirabegron
can be maintained for about 30-minutes to about 10 hours, or
longer.
[0166] In embodiments, the .beta.-form crystal of mirabegron can be
isolated using any techniques, such as decantation, filtration by
gravity or suction, centrifugation, or the solvent can be
evaporated from the mass to obtain the desired product, and
optionally the solid can be washed with a solvent, such as an
anti-solvent or the solvent, to reduce the amount of entrained
impurities.
[0167] In embodiments, the .beta.-form crystal of mirabegron that
is isolated can be dried at suitable temperatures, and atmospheric
or reduced pressures, for about 1-50 hours, or longer, using any
types of drying equipment, such as a tray dryer, vacuum oven, air
oven, fluidized bed dryer, spin flash dryer, flash dryer, and the
like. Drying temperatures and times will be sufficient to achieve
desired product purity.
[0168] In an aspect, the present invention provides a process for
the preparation of .beta.-form crystal of mirabegron
comprising:
[0169] a) providing a solution of mirabegron in a solvent selected
from dimethylsulfoxide, morpholine, ethyl acetate, or mixtures
thereof;
[0170] b) adding an anti-solvent selected from the group of
n-heptane and water to the solution obtained from step a), and
[0171] c) isolating .beta.-form crystal of mirabegron.
[0172] Step a) involves the preparation of a solution of mirabegron
by dissolving the mirabegron in a suitable inert solvent. The
suitable solvent for making a solution can be selected from
dimethylsulfoxide, morpholine, ethyl acetate, or mixture of one or
more thereof. In embodiments, a solution of mirabegron can be
prepared at any suitable temperatures, such as about 0.degree. C.
to about the reflux temperature of the solvent used. Stirring and
heating may be used to reduce the time required for the dissolution
process.
[0173] In embodiments, a solution of mirabegron may be filtered to
make it clear, free of unwanted particles. In embodiments, the
obtained solution may be optionally treated with an adsorbent
material, such as carbon and/or hydrose, to remove colored
components, etc., before filtration.
[0174] In embodiments of step b) the anti-solvent may be added to
the solution obtained in step a). The anti-solvent can be added to
the solution drop-wise, lot wise in one or more lots or rapidly.
The anti-solvents may be selected from n-heptane and water.
[0175] In embodiments, slurry obtained by the precipitation
comprising .beta.-form crystal of mirabegron and inert solvent can
be maintained at any suitable temperatures, such as about
-10.degree. C. to about 40.degree. C., or about 0.degree. C. to
about 35.degree. C. In embodiments, slurry comprising mirabegron
can be maintained for about 30 minutes to about 10 hours, or
longer.
[0176] In embodiments, the .beta.-form crystal of mirabegron can be
isolated using any techniques, such as decantation, filtration by
gravity or suction, centrifugation, or the solvent can be
evaporated from the mass to obtain the desired product, and
optionally the solid can be washed with a solvent, such as an
anti-solvent or the solvent, to reduce the amount of entrained
impurities.
[0177] In embodiments, .beta.-form crystal of mirabegron that is
isolated can be dried at suitable temperatures, and atmospheric or
reduced pressures, for about 1-50 hours, or longer, using any types
of drying equipment, such as a tray dryer, vacuum oven, air oven,
fluidized bed dryer, spin flash dryer, flash dryer, and the like.
Drying temperatures and times will be sufficient to achieve desired
product purity.
[0178] In an aspect, the present invention provides a process for
the preparation of .beta.-form crystal of mirabegron
comprising:
[0179] a) dissolving mirabegron in methanol to provide a
solution;
[0180] b) adding water to the solution obtained in step a)
[0181] c) isolating .beta.-form crystal of mirabegron.
[0182] In embodiments of step a) the solution of mirabegron can be
obtained by dissolving the mirabegron in methanol. Stirring and
heating may be used to reduce the time required for the dissolution
process.
[0183] In embodiments, a solution of mirabegron may be filtered to
make it clear, free of unwanted particles. In embodiments, the
obtained solution may be optionally treated with an adsorbent
material, such as carbon and/or hydrose, to remove colored
components, etc., before filtration.
[0184] In embodiments of step b) water can be added to the solution
obtained in step a). The addition of water to the solution can be
drop-wise, lot-wise in one lot or more lots.
[0185] In embodiments of step c), the .beta.-form crystal of
mirabegron can be isolated by the techniques known in the art such
as filtration. In embodiments, the .beta.-form crystal of
mirabegron can be optionally dried at the suitable temperature and
pressure for a suitable time.
[0186] In embodiments, amorphous mirabegron, solid dispersion of
amorphous mirabegron, .alpha. form crystal of mirabegron and
.beta.-form crystal of mirabegron obtained from the present
invention may be optionally milled to get desired particle sizes.
Milling or micronization may be performed before drying, or after
the completion of drying of the product. Techniques that may be
used for particle size reduction include, without limitation, ball,
roller and hammer mills, and jet mills.
[0187] In an aspect of the invention mirabegron obtained according
to certain processes of the present invention has a particle size
distribution wherein: mean particle size is less than about 200
.mu.m or less than about 100 .mu.m; d (0.5) is less than about 200
.mu.m or less than about 25 .mu.m; and d (0.9) is less than about
500 .mu.m or less than about 50 .mu.m.
[0188] In an aspect of the invention, mirabegron prepared according
to the precesses of the present invention can be substantially pure
having a chemical purity greater than about 99%, or greater than
about 99.5%, or greater than about 99.9%, by weight, as determined
using high performance liquid chromatography (HPLC). Mirabegron
produced by a method of present invention can be chemically pure
mirabegron having purity greater than about 99.5% and containing no
single impurity in amounts greater than about 0.15%, by HPLC.
Mirabegron produced by the methods of present invention can be
chemically pure mirabegron having purity greater than about 99.8%
and containing no single impurity in amounts greater than about
0.1%, by HPLC.
[0189] In an aspect of the invention, mirabegron obtained by the
methods of the present invention can be further purified by using
techniques known in the art to enhance its chemical purity and
chiral purity.
[0190] Mirabegron which is used as a starting material in the
present invention can be in any physical form such as crystalline,
amorphous, mixture of crystalline and amorphous, solvates, hydrates
etc., Mirabegron that may be used as the input for the processes of
the present invention may be obtained by any process including the
processes described in the art and optionally can be purified using
any method known in the art to enhance its chemical purity. For
example mirabegron may be prepared by the processes described in
U.S. Pat. No. 6,346,532 or U.S. Pat. No. 7,342,117.
[0191] In an aspect, present invention also provides a
pharmaceutical composition comprising amorphous form of mirabegron
along with one or more pharmaceutically acceptable carriers,
excipients, or diluents.
[0192] In an aspect, the present invention also provides
pharmaceutical composition comprising solid dispersions of
amorphous mirabegron together with one or more pharmaceutically
acceptable excipients.
[0193] In an aspect, the present invention also provides
pharmaceutical composition comprising the .alpha.-form crystal of
mirabegron obtained according to the any of the processes described
in this application.
[0194] A solid dispersion of mirabegron together with one or more
pharmaceutically acceptable excipients of the present invention may
be further formulated as: solid oral dosage forms such as, but not
limited to: powders, granules, pellets, tablets, and capsules;
liquid oral dosage forms such as but not limited to syrups,
suspensions, dispersions, and emulsions; and injectable
preparations such as but not limited to solutions, dispersions, and
freeze dried compositions. Formulations may be in the forms of
immediate release, delayed release or modified release. Further,
immediate release compositions may be conventional, dispersible,
chewable, mouth dissolving, or flash melt preparations, and
modified release compositions that may comprise hydrophilic or
hydrophobic, or combinations of hydrophilic and hydrophobic,
release rate controlling substances to form matrix or reservoir or
combination of matrix and reservoir systems. The compositions may
be prepared using techniques such as direct blending, dry
granulation, wet granulation, and extrusion and spheronization.
Compositions may be presented as uncoated, film coated, sugar
coated, powder coated, enteric coated, and modified release coated.
Compositions of the present invention may further comprise one or
more pharmaceutically acceptable excipients.
[0195] Pharmaceutically acceptable excipients that are useful in
the present invention include, but are not limited to: diluents
such as starches, pregelatinized starches, lactose, powdered
celluloses, microcrystalline celluloses, dicalcium phosphate,
tricalcium phosphate, mannitol, sorbitol, sugar or the like;
binders such as acacia, guar gum, tragacanth, gelatin,
polyvinylpyrrolidones, hydroxypropyl celluloses, hydroxypropyl
methylcelluloses, pregelatinized starches or the like;
disintegrants such as starches, sodium starch glycolate,
pregelatinized starches, crospovidones, croscarmellose sodium,
colloidal silicon dioxide or the like; lubricants such as stearic
acid, magnesium stearate, zinc stearate or the like; glidants such
as colloidal silicon dioxide or the like; solubility or wetting
enhancers such as anionic or cationic or neutral surfactants;
complex forming agents such as various grades of cyclodextrins and
resins; release rate controlling agents such as hydroxypropyl
celluloses, hydroxymethyl celluloses, hydroxypropyl
methylcelluloses, ethylcelluloses, methylcelluloses, various grades
of methyl methacrylates, waxes or the like. Other pharmaceutically
acceptable excipients that are of use include but are not limited
to film formers, plasticizers, colorants, flavoring agents,
sweeteners, viscosity enhancers, preservatives, antioxidants, or
the like.
DEFINITIONS
[0196] The following definitions are used in connection with the
present invention unless the context indicates otherwise. The term
"amorphous" refers to a solid lacking any long-range translational
orientation symmetry that characterizes crystalline structures
although; it may have short range molecular order similar to a
crystalline solid. The term "anti-solvent" refers to a liquid that,
when combined with a solution of mirabegron, reduces solubility of
the mirabegron in the solution, causing crystallization or
precipitation in some instances spontaneously, and in other
instances with additional steps, such as seeding, cooling,
scratching and/or concentrating. Celite.RTM. is flux-calcined
diatomaceous earth. Celite.RTM. is a registered trademark of World
Minerals Inc. Hyflow is flux-calcined diatomaceous earth treated
with sodium carbonate. Hyflo Super Cel.TM. is a registered
trademark of the Manville Corp. Polymorphs are different solids
sharing the same molecular formula, yet having distinct physical
properties when compared to other polymorphs of the same formula.
Povidone K-90 is poly(1-vinyl-2-pyrrolidinone) with an average M.W.
of 360,000.
[0197] An "alcohol solvent" is an organic solvent containing a
carbon bound to a hydroxyl group. "Alcoholic solvents" include, but
are not limited to, methanol, ethanol, 2-nitroethanol,
2-fluoroethanol, 2,2,2-trifluoroethanol, hexafluoroisopropyl
alcohol, ethylene glycol, 1-propanol, 2-propanol (isopropyl
alcohol), 2-methoxyethanol, 1-butanol, 2-butanol, i-butyl alcohol,
t-butyl alcohol, 2-ethoxyethanol, diethylene glycol, 1-, 2-, or
3-pentanol, neo-pentyl alcohol, t-pentyl alcohol, diethylene glycol
monomethyl ether, diethylene glycol monoethyl ether, cyclohexanol,
benzyl alcohol, phenol, glycerol, C.sub.1-6alcohols, or the
like.
[0198] An "aliphatic or alicyclic hydrocarbon solvent" refers to a
liquid, non-aromatic, hydrocarbon, which may be linear, branched,
or cyclic. It is capable of dissolving a solute to form a uniformly
dispersed solution. Examples of a hydrocarbon solvents include, but
are not limited to, n-pentane, isopentane, neopentane, n-hexane,
isohexane, 3-methylpentane, 2,3-dimethylbutane, neohexane,
n-heptane, isoheptane, 3-methylhexane, neoheptane,
2,3-dimethylpentane, 2,4-dimethylpentane, 3,3-dimethylpentane,
3-ethylpentane; 2,2,3-trimethylbutane, n-octane, isooctane,
3-methylheptane, neooctane, cyclohexane, methylcyclohexane,
cycloheptane, C.sub.5-C.sub.8aliphatic hydrocarbons, petroleum
ethers, or mixtures thereof.
[0199] "Aromatic hydrocarbon solvent" refers to a liquid,
unsaturated, cyclic, hydrocarbon containing one or more rings which
has at least one 6-carbon ring containing three double bonds. It is
capable of dissolving a solute to form a uniformly dispersed
solution. Examples of aromatic hydrocarbon solvents include, but
are not limited to, benzene toluene, ethylbenzene, m-xylene,
o-xylene, p-xylene, indane, naphthalene, tetralin,
trimethylbenzene, chlorobenzene, fluorobenzene, trifluorotoluene,
anisole, C.sub.6-C.sub.10aromatic hydrocarbons, or mixtures
thereof.
[0200] An "ester solvent" is an organic solvent containing a
carboxyl group --(C.dbd.O)--O-- bonded to two other carbon atoms.
"Ester solvents" include, but are not limited to, ethyl acetate,
n-propyl acetate, n-butyl acetate, isobutyl acetate, t-butyl
acetate, ethyl formate, methyl acetate, methyl propanoate, ethyl
propanoate, methyl butanoate, ethyl butanoate, C.sub.3-6esters, or
the like.
[0201] A "halogenated hydrocarbon solvent" is an organic solvent
containing a carbon bound to a halogen. "Halogenated hydrocarbon
solvents" include, but are not limited to, dichloromethane,
1,2-dichloroethane, trichloroethylene, perchloroethylene,
1,1,1-trichloroethane, 1,1,2-trichloroethane, chloroform, carbon
tetrachloride, or the like.
[0202] A "ketone solvent" is an organic solvent containing a
carbonyl group --(C.dbd.O)-- bonded to two other carbon atoms.
"Ketone solvents" include, but are not limited to, acetone, ethyl
methyl ketone, diethyl ketone, methyl isobutyl ketone,
C.sub.3-6ketones, 4-methyl-pentane-2-one or the like.
[0203] A "nitrile solvent" is an organic solvent containing a cyano
--(C.ident.N) bonded to another carbon atom. "Nitrile solvents"
include, but are not limited to, acetonitrile, propionitrile,
C.sub.2-6nitriles, or the like.
[0204] A "polar aprotic solvent" has a dielectric constant greater
than 15 and is at least one selected from the group consisting of
amide-based organic solvents, such as N,N-dimethylformamide (DMF),
N,N-dimethylacetamide (DMA), N-methylpyrrolidone (NMP), formamide,
acetamide, propanamide, hexamethyl phosphoramide (HMPA), and
hexamethyl phosphorus triamide (HMPT); nitro-based organic
solvents, such as nitromethane, nitroethane, nitropropane, and
nitrobenzene; pyridine-based organic solvents, such as pyridine and
picoline; sulfone-based solvents, such as dimethylsulfone,
diethylsulfone, diisopropylsulfone, 2-methylsulfolane,
3-methylsulfolane, 2,4-dimethylsulfolane, 3,4-dimethy sulfolane,
3-sulfolene, and sulfolane; and sulfoxide-based solvents such as
dimethylsulfoxide (DMSO).
[0205] An "ether solvent" is an organic solvent containing an
oxygen atom --O-bonded to two other carbon atoms. "Ether solvents"
include, but are not limited to, diethyl ether, diisopropyl ether,
methyl t-butyl ether, glyme, diglyme, tetrahydrofuran,
2-methyltetrahydrofuran, 1,4-dioxane, dibutyl ether, dimethylfuran,
2-methoxyethanol, 2-ethoxyethanol, anisole, C.sub.2-6ethers, or the
like.
[0206] Certain specific aspects and embodiments of the present
invention will be explained in more detail with reference to the
following examples, which are provided for purposes of illustration
only and should not be construed as limiting the scope of the
present invention in any manner.
EXAMPLES
[0207] All PXRD data reported herein are obtained using a Bruker
AXS D8 Advance Powder X-ray Diffractometer or a PANalytical X-ray
Diffractometer, using copper K.alpha. radiation.
Example 1
Preparation of Amorphous Form of Mirabegron
[0208] Mirabegron (1.0 g) and acetone (160 mL) were charged in to a
round-bottom flask at 25-35.degree. C. The contents were heated to
40-53.degree. C. and stirred to dissolve mirabegron completely. The
resulting solution was evaporated completely in Buchi.RTM.
Rotavapor.RTM. at 40-45.degree. C. under reduced pressure to afford
800 mg of the title compound. PXRD pattern is shown as FIG. 1.
Example 2
Preparation of a Solid Dispersion of Amorphous Mirabegron with
Povidone
[0209] Mirabegron (500 mg) and 4-methylpentane-2-one (35.0 mL) were
charged in to a round bottom flask at 25-35.degree. C. The contents
were heated to 70-75.degree. C. and stirred to dissolve mirabegron
completely. Povidone K-90 (500 mg) and n-heptane (90 mL) were
charged in to another round bottom flask at 25-35.degree. C. and
stirred for 5-10 minutes. The reaction mixture was cooled to 5 to
10.degree. C. Above obtained solution of mirabegron in
4-methylpentane-2-one was charged to the mixture at 5-10.degree. C.
and the reaction mixture was stirred for 10-15 minutes. The
obtained solid was collected by filtration, washed with n-heptane
(5 mL) to afford 1.10 g of the title material. PXRD pattern is
shown as FIG. 2.
Example 3
Preparation of a Solid Dispersion of Amorphous Mirabegron with
Povidone
[0210] Mirabegron (1.0 g) and acetone (160 mL) were charged in to a
round bottom flask at 25-35.degree. C. The contents were heated to
50-53.degree. C. and stirred to dissolve mirabegron completely. The
resulting solution was evaporated completely in Buchi.RTM.
Rotavapor.RTM. at 40-45.degree. C. under reduced pressure.
Dichloromethane (180 mL) was charged to the reaction mass and
stirred at 38-39.degree. C. Povidone K-90 (1.0 g) and
dichloromethane (50 mL) were charged in to another round bottom
flask at 25-35.degree. C. The contents were heated to 35-38.degree.
C. and stirred to dissolve povidone-K-90 completely. The resultant
solution of povidone-K-90 in dichloromethane was charged to the
above obtained solution of mirabegron in dichloromethane at
30-35.degree. C. The reaction mixture was stirred at 30-35.degree.
C. for 10-15 minutes. The solvent from the mixture was evaporated
under reduced pressure at 35-40.degree. C. to afford 1.82 g of the
title material.
[0211] PXRD pattern is shown as FIG. 3.
Example 4
Preparation of a Solid Dispersion of Amorphous Mirabegron with
Povidone (1:1)
[0212] Mirabegron (7.0 g), Povidone K-90 (7.0 g) and methanol (700
mL) were charged in to a round-bottom flask at 27.degree. C. The
contents were stirred at 27.degree. C. to obtain clear solution.
The resulting solution was evaporated completely in Buchi.RTM.
Rotavapor.RTM. at 50-55.degree. C. under reduced pressure to afford
12.0 g of the title compound. PXRD pattern is shown as FIG. 3.
Example 5
Preparation of a Solid Dispersion of Amorphous Mirabegron with
Povidone (2:1)
[0213] Mirabegron (9.0 g), Povidone K-90 (4.5 g) and methanol (700
mL) were charged in to a round-bottom flask at 27.degree. C. The
contents were stirred at 27.degree. C. to obtain clear solution.
The resulting solution was evaporated completely in Buchi.RTM.
Rotavapor.RTM. at 50-55.degree. C. under reduced pressure to afford
11.5 g of the title compound. PXRD pattern is shown as FIG. 3.
Example 6
Preparation of .beta.-Form Crystal of Mirabegron
[0214] Mirabegron (500 mg) and tetrahydrofuran (20 mL) were charged
into a round bottom flask at 27.degree. C. The obtained suspension
was stirred and heated to 40.degree. C. to get a clear solution.
The clear solution was added to the methylcyclohexane (40 mL) at
10.degree. C. and stirred for 15 minutes at the same temperature.
The precipitated solid was collected by filtration and washed with
methylcyclohexane (5 mL) and dried to afford 180 mg of the title
compound.
Examples 7-13
Preparation of .beta.-Form Crystal of Mirabegron
[0215] Mirabegron (500 mg) and a solvent were charged into a round
bottom flask. The mixture was stirred to obtain a clear solution.
If required, the mixture was heated to obtain a clear solution. The
clear solution was added to an anti-solvent. The mass was
maintained to precipitate the solid (if required, using cooling)
and the formed solid was collected by filtration, washed with a
small quantity of anti-solvent, and then dried to produce
.beta.-form crystal of mirabegron. The following examples
illustrate the preparation of .beta.-form crystal of mirabegron
following this procedure.
TABLE-US-00001 Solvent Anti-solvent Yield Example (mL) (mL) (mg) 7
Tetrahydrofuran (20) n-Heptane (40) 280 8 N,N-dimethylformamide
(10) water (30) 280 9 Formamide (20) water (40) 310 10
N,N-dimethylacetamide (10) water (30) 380 11 Tetrahydrofuran (20)
Toluene (40) 310 12 2-methoxyethanol (20) water (40) 380 13
Morpholine (10) n-Heptane (30) 410
Examples 14-17
Preparation of .beta.-Form Crystal of Mirabegron
[0216] Mirabegron (500 mg) and a solvent were charged into a round
bottom flask. The mixture was stirred to obtain a clear solution.
If required, the mixture was heated to obtain a clear solution. The
clear solution was cooled if required. An anti-solvent was added to
the solution. The mass was maintained to precipitate a solid (if
required, using cooling) and the formed solid was collected by
filtration, washed with a small quantity of anti-solvent and then
dried to produce .beta.-form crystal of mirabegron. The following
examples illustrate the preparation of .beta.-form crystal of
mirabegron, following this procedure.
TABLE-US-00002 Solvent Anti-solvent Yield Example (mL) (mL) (mg) 14
Methanol (10) water (40) 410 15 Dimethylsulfoxide (3) water (15)
420 16 Morpholine (0.5) and water (50) 380 N-methylpyrolidine (15)
17 Ethyl acetate (120) and n-Heptane (240) 410 water (0.5)
Examples 18
Preparation of .beta.-Form Crystal of Mirabegron
[0217] Mirabegron (1.0 g) and Methyl isobutyl ketone (230 mL) were
charged into a round bottom flask at 27.degree. C. The obtained
suspension was stirred and heated to 70.degree. C. to get a clear
solution. The solution was cooled to 27.degree. C. under stirring
and further cooled to 5.degree. C. and stirred for 10 minutes at
5.degree. C. The precipitated solid compound was filtered and
washed with methyl isobutyl ketone (5 mL) and dried under suction
for 5 minutes to obtain 410 mg of the title compound.
Examples 19-34
Preparation of .alpha.-Form Crystal of Mirabegron
[0218] Mirabegron (500 mg) and a solvent were charged into a round
bottom flask. The mixture was stirred to obtain a clear solution.
If required, the mixture was heated to obtain a clear solution. An
anti-solvent was added to the solution. The mass was maintained to
precipitate the solid (if required, using cooling) and the formed
solid was collected by filtration, washed with a small quantity of
anti-solvent, and then dried to produce .alpha.-form crystal of
mirabegron. The following examples illustrate the preparation of
.alpha.-form crystal of mirabegron following this procedure.
TABLE-US-00003 Solvent Anti-solvent Yield Example (mL) (mL) (mg) 19
Tetrahydrofuran (20) Methylcyclohexane 360 (40) 20 Tetrahydrofuran
(20) Cyclohexane (40) 400 21 Tetrahydrofuran (20) Water (40) 310 22
Tetrahydrofuran (20) Diisopropyl ether 320 (40) 23 Tetrahydrofuran
(20) Toluene (40) 150 24 Methanol (10) Methyl tertiary butyl 410
ether (40) 25 Methanol (10) Diisopropyl ether (40) 320 26 Ethanol
(0.5) and Methylcyclohexane 480 acetone (70) (150) 27 Acetonitrile
(0.5) and Methylcyclohexane 380 Methylisobutylketone (50) (150) 28
Acetonitrile (0.5) and n-Heptane (120) 280 Tetrahydrofuran (60) 29
1,4-Dioxane (0.5) and Methylcyclohexane 380 Acetone (70) (150) 30
Chlorobenzene (0.5) and Methylcyclohexane 380 Methyl isobutyl
ketone (120) (140) 31 Chlorobenzene (0.5) and n-Heptane (120) 280
Tetrahydrofuran (60) 32 Methanol (0.2) and n-Heptane (150) 480
Methyl isobutyl ketone (70) 33 Methanol (0.2) and Methylcyclohexane
410 Tetrahydrofuran (60) (120) 34 Water (0.5) and Cyclohexane (240)
410 Methyl isobutyl ketone (120)
Examples 35-40
Preparation of .alpha.-Form Crystal of Mirabegron
[0219] Mirabegron (100 mg) and a solvent were charged into a round
bottom flask. The mixture was stirred to obtain a clear solution.
If required, the mixture was heated to obtain a clear solution. The
clear solution was kept for slow evaporation at room temperature to
produce .alpha.-form crystal of mirabegron. The following examples
illustrate the preparation of .alpha.-form crystal of mirabegron
following this procedure.
TABLE-US-00004 Solvent Yield Example (mL) (mg) 35 2-Butanol (16) 88
36 Ethanol (12) 92 37 Isopropyl alcohol (20) 80 38 Chlorobenzene
(15) 90 39 Ethyl acetate (20 mL) 80 40 Tetrahydrofuran (5) 90
Examples 41
Preparation of .alpha.-Form Crystal of Mirabegron
[0220] Mirabegron (500 mg) and acetone (15 mL) were charged into a
round bottom flask at 27.degree. C. The obtained suspension was
stirred and heated to 50.degree. C. to get a clear solution. The
clear solution was added to methylcyclohexane (50 mL) at 5.degree.
C. and stirred for 15 minutes at the same temperature. The solution
was kept for the slow evaporation of solvent at room temperature.
The obtained solid was collected by filtration and washed with
methylcyclohexane (5 mL). The material was dried under suction at
27.degree. C. for 5 minutes to afford 280 mg of the title
compound.
Examples 42
Preparation of .alpha.-Form Crystal of Mirabegron
[0221] Mirabegron (1.0 g) and tetrahydrofuran (80 mL) were charged
into a round bottom flask at 27.degree. C. The obtained suspension
was stirred and heated to 70.degree. C. to get a clear solution.
The solution was cooled to 27.degree. C. under stirring in 25
minutes and further cooled to 5.degree. C. and stirred for 10
minutes at 5.degree. C. The precipitated solid compound was
filtered and washed with tetrahydrofuran (5 mL) and dried under
suction for 5 minutes to obtain 410 mg of the title compound.
Examples 43
Preparation of .alpha.-Form Crystal of Mirabegron
[0222] Mirabegron (500 mg) and ethyl acetate (140 mL) were charged
into a round bottom flask at 27.degree. C. The obtained suspension
was stirred and heated to 65.degree. C. to get a clear solution.
The solution was cooled to 27.degree. C. under stirring in 25
minutes and further cooled to 5.degree. C. and stirred for 10
minutes at 5.degree. C. The precipitated solid compound was
filtered and washed with ethyl acetate (5 mL) and dried under
suction for 5 minutes to obtain 218 mg of the title compound.
Examples 44
Preparation of .alpha.-Form Crystal of Mirabegron
[0223] Mirabegron (500 mg) and toluene (100 mL) were charged into a
round bottom flask at 27.degree. C. The obtained suspension was
stirred and heated to 110.degree. C. to get a clear solution. The
solution was cooled to 27.degree. C. under stirring in 30 minutes
and further cooled to 5.degree. C. and stirred for 10 minutes at
5.degree. C. The precipitated solid compound was filtered and
washed with toluene (5 mL) and dried under suction for 5 minutes to
obtain 470 mg of the title compound
Examples 45
Preparation of .alpha.-Form Crystal of Mirabegron
[0224] Mirabegron (3 g), methanol (12 mL) and water (12 mL) were
charged into a round bottom flask at 26.degree. C. The obtained
suspension was stirred and heated to 62.degree. C. to get a clear
solution. The clear solution was cooled to 27.degree. C. and
stirred for 3 hours at the same temperature. The precipitated solid
was collected by filtration and washed with water (5 mL) and dried
under vacuum at 70.degree. C. for 4 hours. Yield: 2.0 g.
Examples 46
Preparation of .alpha.-Form Crystal of Mirabegron
[0225] Mirabegron (2.0 g) and methanol (6 mL) were charged into a
round bottom flask at 27.degree. C. The obtained suspension was
stirred and heated to 63.degree. C. to get a clear solution. The
solution was cooled to 27.degree. C. under stirring in 1 hour and
stirred for 2 hours and 30 30 minutes at 27.degree. C. The
precipitated solid compound was filtered and dried under vacuum at
50.degree. C. for 2 hours to obtain 1.1 g of the title
compound.
Examples 47
Preparation of .alpha.-Form Crystal of Mirabegron
[0226] Mirabegron (2.0 g) and ethanol (20 mL) were charged into a
round bottom flask at 27.degree. C. The obtained suspension was
stirred and heated to 75.degree. C. to get a clear solution. The
solution was cooled to 27.degree. C. under stirring in 1 hour and
stirred for 2 hours at 27.degree. C. The precipitated solid
compound was filtered and dried under vacuum at 50.degree. C. for 2
hours and 30 minutes to obtain 1.2 g of the title compound.
* * * * *